Skip to main content Accessibility help

Altered top-down and bottom-up processing of fear conditioning in panic disorder with agoraphobia

  • U. Lueken (a1), B. Straube (a2), I. Reinhardt (a3), N. I. Maslowski (a1), H.-U. Wittchen (a1), A. Ströhle (a4), A. Wittmann (a4), B. Pfleiderer (a5), C. Konrad (a2), A. Ewert (a5), C. Uhlmann (a6), V. Arolt (a6), A. Jansen (a2) and T. Kircher (a2)...

Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients.


The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls.


Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation.


The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.

Corresponding author
* Address for correspondence: Prof. Dr. T. Kircher, Department of Psychiatry and Psychotherapy, Philipps University Marburg, Rudolf-Bultmann-Straße 8, D-35039 Marburg, Germany. (Email:
Hide All
Amaral, DG, Price, JC, Pitkänen, A, Carmichael, ST (1992). Anatomical organization of the primate amygdaloid complex. In The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction (ed. Aggleton, J. P.), pp. 166. Wiley-Liss: New York.
An, X, Bandler, R, Ongur, D, Price, JL (1998). Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in macaque monkeys. Journal of Comparative Neurology 401, 455479.
APA (2000). Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision (DSM-IV-TR). American Psychiatric Association: Washington, DC.
Aron, AR, Fletcher, PC, Bullmore, ET, Sahakian, BJ, Robbins, TW (2003). Stop-signal inhibition disrupted by damage to right inferior frontal gyrus in humans. Nature Neuroscience 6, 115116.
Beck, AT, Steer, RA, Brown, GK (1996). Beck Depression Inventory, Second Edition. The Psychological Corporation: San Antonio, TX.
Bernstein, A, Zvolensky, MJ, Marshall, EC, Schmidt, NB (2009). Laboratory test of a novel structural model of anxiety sensitivity and panic vulnerability. Behavior Therapy 40, 171180.
Boshuisen, ML Ter Horst, GJ, Paans, AMJ, Reinders, AATS, Den Boer, JA (2002). rCBF differences between panic disorder patients and control subjects during anticipatory anxiety and rest. Biological Psychiatry 52, 126135.
Bouton, ME, Mineka, S, Barlow, DH (2001). A modern learning theory perspective on the etiology of panic disorder. Psychological Review 108, 432.
Bradley, MM, Lang, PJ (1994). Measuring emotion: the Self-Assessment Manikin and the Semantic Differential. Journal of Behavior Therapy and Experimental Psychiatry 25, 4959.
Brandao, ML, Zanoveli, JM, Ruiz-Martinez, RC, Oliveira, LC, Landeira-Fernandez, J (2008). Different patterns of freezing behavior organized in the periaqueductal gray of rats: association with different types of anxiety. Behavioural Brain Research 188, 113.
Dresler, T, Guhn, A, Tupak, SV, Ehlis, AC, Herrmann, MJ, Fallgatter, AJ, Deckert, J, Domschke, K (2012). Revise the revised? New dimensions of the neuroanatomical hypothesis of panic disorder. Journal of Neural Transmission 120, 329.
Etkin, A, Wager, TD (2007). Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. American Journal of Psychiatry 164, 14761488.
Friedman, L, Glover, GH, Krenz, D, Magnotta, V (2006). Reducing inter-scanner variability of activation in a multicenter fMRI study: role of smoothness equalization. NeuroImage 32, 16561668.
Fujiwara, A, Yoshida, T, Otsuka, T, Hayano, F, Asami, T, Narita, H, Nakamura, M, Inoue, T, Hirayasu, Y (2011). Midbrain volume increase in patients with panic disorder. Psychiatry and Clinical Neurosciences 65, 365373.
Gloster, AT, Wittchen, HU, Einsle, F, Hofler, M, Lang, T, Helbig-Lang, S, Fydrich, T, Fehm, L, Hamm, AO, Richter, J, Alpers, GW, Gerlach, AL, Strohle, A, Kircher, T, Deckert, J, Zwanzger, P, Arolt, V (2009). Mechanism of action in CBT (MAC): methods of a multi-center randomized controlled trial in 369 patients with panic disorder and agoraphobia. European Archives of Psychiatry and Clinical Neuroscience 259 (Suppl. 2), S155S166.
Gorman, JM, Kent, JM, Sullivan, GM, Coplan, JD (2000). Neuroanatomical hypothesis of panic disorder, revised. American Journal of Psychiatry 157, 493505.
Graeff, FG, Del Ben, CM (2008). Neurobiology of panic disorder: from animal models to brain neuroimaging. Neuroscience and Biobehavioral Reviews 32, 13261335.
Guy, W (1976). ECDEU Assessment Manual for Psychopharmacology. U.S. National Institute of Health, Psychopharmacology Research Branch: Rockville, MD.
Kircher, T, Arolt, V, Jansen, A, Pyka, M, Reinhardt, I, Kellermann, T, Konrad, C, Lueken, U, Gloster, AT, Gerlach, AL, Ströhle, A, Wittmann, A, Pfleiderer, B, Wittchen, HU, Straube, T (2013). Effect of cognitive behavioural therapy on neural correlates of fear conditioning in panic disorder. Biological Psychiatry 73, 93101.
LeDoux, JE, Iwata, J, Cicchetti, P, Reis, DJ (1988). Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. Journal of Neuroscience 8, 25172529.
Lenartowicz, A, Verbruggen, F, Logan, GD, Poldrack, RA (2011). Inhibition-related activation in the right inferior frontal gyrus in the absence of inhibitory cues. Journal of Cognitive Neuroscience 23, 33883399.
Lissek, S (2012). Toward an account of clinical anxiety predicated on basic, neurally mapped mechanisms of Pavlovian fear-learning: the case for conditioned overgeneralization. Depression and Anxiety 29, 257263.
Lissek, S, Powers, AS, McClure, EB, Phelps, EA, Woldehawariat, G, Grillon, C, Pine, DS (2005). Classical fear conditioning in the anxiety disorders: a meta-analysis. Behaviour Research and Therapy 43, 13911424.
Lissek, S, Rabin, SJ, McDowell, DJ, Dvir, S, Bradford, DE, Geraci, M, Pine, DS, Grillon, C (2009). Impaired discriminative fear-conditioning resulting from elevated fear responding to learned safety cues among individuals with panic disorder. Behaviour Research and Therapy 47, 111118.
Lovick, TA (2000). Panic disorder – a malfunction of multiple transmitter control systems within the midbrain periaqueductal gray matter? Neuroscientist 6, 4859.
Lueken, U, Muehlhan, M, Wittchen, HU, Kellermann, T, Reinhardt, I, Konrad, C, Lang, T, Wittmann, A, Strohle, A, Gerlach, AL, Ewert, A, Kircher, T (2011). (Don't) panic in the scanner! How panic patients with agoraphobia experience a functional magnetic resonance imaging session. European Neuropsychopharmacology 21, 516525.
McNaughton, N, Corr, PJ (2004). A two-dimensional neuropsychology of defense: fear/anxiety and defensive distance. Neuroscience and Biobehavioral Reviews 28, 285305.
Michael, T, Blechert, J, Vriends, N, Margraf, J, Wilhelm, FH (2007). Fear conditioning in panic disorder: enhanced resistance to extinction. Journal of Abnormal Psychology 116, 612617.
Mobbs, D, Marchant, JL, Hassabis, D, Seymour, B, Tan, G, Gray, M, Petrovic, P, Dolan, RJ, Frith, CD (2009). From threat to fear: the neural organization of defensive fear systems in humans. Journal of Neuroscience 29, 1223612243.
Mobbs, D, Petrovic, P, Marchant, JL, Hassabis, D, Weiskopf, N, Seymour, B, Dolan, RJ, Frith, CD (2007). When fear is near: threat imminence elicits prefrontal-periaqueductal gray shifts in humans. Science 317, 10791083.
Nichols, T, Brett, M, Andersson, J, Wager, T, Poline, JB (2005). Valid conjunction inference with the minimum statistic. NeuroImage 25, 653660.
Oldfield, RC (1971). The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9, 97113.
Ottaviani, C, Cevolani, D, Nucifora, V, Borlimi, R, Agati, R, Leonardi, M, De Plato, G, Brighetti, G (2012). Amygdala responses to masked and low spatial frequency fearful faces: a preliminary fMRI study in panic disorder. Psychiatry Research 203, 159165.
Protopopescu, X, Pan, H, Tuescher, O, Cloitre, M, Goldstein, M, Engelien, A, Yang, YH, Gorman, J, LeDoux, J, Stern, E, Silbersweig, D (2006). Increased brainstem volume in panic disorder: a voxel-based morphometric study. Neuroreport 17, 361363.
Reinhardt, I, Jansen, A, Kellermann, T, Schuppen, A, Kohn, N, Gerlach, AL, Kircher, T (2010). Neural correlates of aversive conditioning: development of a functional imaging paradigm for the investigation of anxiety disorders. European Archives of Psychiatry and Clinical Neuroscience 260, 443453.
Reiss, S, Peterson, RA, Gursky, DM, McNally, RJ (1986). Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behaviour Research and Therapy 24, 18.
Schmidt, NB, Zvolensky, MJ, Maner, JK (2006). Anxiety sensitivity: prospective prediction of panic attacks and Axis I pathology. Journal of Psychiatric Research 40, 691699.
Sehlmeyer, C, Schoning, S, Zwitserlood, P, Pfleiderer, B, Kircher, T, Arolt, V, Konrad, C (2009). Human fear conditioning and extinction in neuroimaging: a systematic review. Plos One 4, e5865.
Shear, MK, Vander Bilt, J, Rucci, P, Endicott, J, Lydiard, B, Otto, MW, Pollack, MH, Chandler, L, Williams, J, Ali, A, Frank, DM (2001). Reliability and validity of a structured interview guide for the Hamilton Anxiety Rating Scale (SIGH-A). Depression and Anxiety 13, 166178.
Shin, LM, Liberzon, I (2010). The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35, 169191.
Slotnick, SD, Moo, LR, Segal, JB, Hart, J Jr. (2003). Distinct prefrontal cortex activity associated with item memory and source memory for visual shapes. Brain Research. Cognitive Brain Research 17, 7582.
Slotnick, SD, Schacter, DL (2004). A sensory signature that distinguishes true from false memories. Nature Neuroscience 7, 664672.
Swick, D, Ashley, V, Turken, U (2008). Left inferior frontal gyrus is critical for response inhibition. BMC Neuroscience 9, 102.
Tuescher, O, Protopopescu, X, Pan, H, Cloitre, M, Butler, T, Goldstein, M, Root, JC, Engelien, A, Furman, D, Silverman, M, Yang, YH, Gorman, J, LeDoux, J, Silbersweig, D, Stern, E (2011). Differential activity of subgenual cingulate and brainstem in panic disorder and PTSD. Journal of Anxiety Disorders 25, 251257.
Uchida, RR, Del Ben, CM, Busatto, GF, Duran, FLS, Guimaraes, FS, Crippa, JAS, Araujo, D, Santos, AC, Graeff, FG (2008). Regional gray matter abnormalities in panic disorder: a voxel-based morphometry study. Psychiatry Research 163, 2129.
Wilensky, AE, Schafe, GE, Kristensen, MP, LeDoux, JE (2006). Rethinking the fear circuit: the central nucleus of the amygdala is required for the acquisition, consolidation, and expression of Pavlovian fear conditioning. Journal of Neuroscience 26, 1238712396.
Wittchen, HU, Jacobi, F, Rehm, J, Gustavsson, A, Svensson, M, Jonsson, B, Olesen, J, Allgulander, C, Alonso, J, Faravelli, C, Fratiglioni, L, Jennum, P, Lieb, R, Maercker, A, van Os, J, Preisig, M, Salvador-Carulla, L, Simon, R, Steinhausen, HC (2011). The size and burden of mental disorders and other disorders of the brain in Europe 2010. European Neuropsychopharmacology 21, 655679.
Wittchen, HU, Pfister, H (1997). DIA-X Interview. Swets & Zeitlinger: Frankfurt.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed